Hepatitis C virus (HCV) infection affects 170 million people worldwide and results in cirrhosis in approximately 30% of patients after 30 years of chronic infection. HCV infection, alone or in combination with alcohol ingestion to excess, is the leading indication for liver transplantation (LT) in the United States and in Europe. HCV infection is also associated with extrahepatic disease, including mixed essential cryoglobulinemia, membranous glomerulonephritis, porphyria cutanea tarda, autoimmune thyroiditis, and B-cell lymphoma. Some of these extrahepatic manifestations resolve following interferon-induced sustained viral suppression,1 but this treatment option may be contraindicated in patients with end-stage liver disease.2 We report successful treatment of lymphoma arising in gastric mucosa-associated lymphoid tissue (MALToma) in a patient with end-stage liver disease secondary to HCV infection who underwent liver transplantation.
End-stage liver disease due to chronic hepatitis C virus (HCV) infection is now the most frequent indication for liver transplantation. HCV infection is associated with extrahepatic disease including cryoglobulinemia and lymphoma. The number of patients requiring liver transplantation (LT) for cirrhosis secondary to HCV infection has increased over the past 10 years; consequently, associated extrahepatic manifestations (in particular hematological malignancies) will be more commonly observed in this patient group. The management of patients with both end-stage liver disease and significant HCV-related extrahepatic disease is undefined. We report a 59-year-old man in whom extranodal marginal-zone B-cell lymphoma arising in gastric mucosa-associated lymphoid tissue (MALToma) was successfully eradicated by rituximab administration and gastrectomy at LT for HCV-related cirrhosis. Our experience with rituximab in this patient suggests that it can be used safely in the setting of severe liver disease due to HCV infection. Rituximab may be useful in preventing progression of NHL until surgical extirpation is possible. (Liver Transpl 2005;11:839–842.)
A 59-year-old man was referred to the Institute of Liver Studies, King's College Hospital, for consideration of LT for cirrhotic end-stage liver disease secondary to HCV infection. HCV infection (genotype 1b) was diagnosed 3 years earlier following variceal hemorrhage. Synthetic function had deteriorated (Child-Turcotte-Pugh score 9, MELD (Model for End-Stage Liver Disease score) 14 at transplant assessment) with the development of diuretic-resistant ascites requiring fortnightly paracentesis. In addition, the patient had experienced a single episode of spontaneous bacterial peritonitis. Rheumatoid factor was present at 86.9 IU/mL and type 2 cryoglobulinemia was detected; autoantibodies were not identified.
Six weeks after listing, he presented with symptoms of abdominal bloating. He reported tarry stools. Endoscopy identified extensive antral ulceration and a polypoid mass in the body and antrum of the stomach (Fig. 1); microscopy of biopsy specimens identified low-grade MALToma. Microorganisms consistent with Helicobacter pylori were seen. Computerized tomograms demonstrated a fundic soft-tissue mass and gastric mucosal thickening. Extragastric involvement was not identified. No abnormality was found on bone marrow biopsy. First-line therapy, instigated at his referring hospital, consisted of Helicobacter eradication (lansoprazole 30 mg twice daily, amoxicillin 1 g twice daily, and clarithromycin 1 g twice daily for 7 days) followed by administration of chlorambucil. Endoscopic follow-up 28 days later with histologic review did not demonstrate a response to treatment. The patient returned to King's College Hospital for further management.
Endoscopic sonography demonstrated a thickened gastric wall with infiltration of the submucosa and muscularis propria (Fig. 2). Serosal invasion could not be excluded. Lymphadenopathy was not identified.
Renal impairment (creatinine clearance 48 mL/min; 30% function, left kidney, by MAG-3 scan) and persistent ascites precluded radiotherapy. Rituximab (Mabthera; 375 mg/m2; Roche Pharma, Basel, Switzerland) a monoclonal antibody directed against the B-cell antigen CD20 was administered weekly on 4 consecutive weeks. However, repeat endoscopy found no macroscopic improvement in the gastric lesions, and subtotal gastrectomy was planned as definitive therapy after liver transplantation.
One month after completing rituximab therapy whole-graft LT was performed. Immunosuppression consisted of tacrolimus-based dual therapy with prednisolone (standard protocol); doses were adjusted to maintain desired blood levels (tacrolimus 5-15 ng/mL; trough samples taken 12 hours postdose) for the first year. Prednisolone was commenced at a daily dose of 20 mg, reducing by 5 mg every week after the second week, and withdrawn completely at 3 months. At surgery no extragastric malignancy was found, and recovery was uncomplicated. Following LT, endoscopy at 3 and 24 weeks confirmed persistent polypoid masses within the body and antrum of the stomach. While biopsy specimens contained no tumor, a subtotal gastrectomy was performed 5 months after LT, as persistence of MALToma within the masses could not be excluded. The mucosa of the resected stomach included several greater-curvature polyps (0.5-1.2 cm diameter); microscopy identified both acute inflammatory infiltrates and dense lymphocyte inflammatory infiltrates. There was no evidence of lymphoma. Epithelial foveolar hyperplasia was noted. Helicobacter forms were not observed.
Biopsy specimens taken at endoscopy and at gastrectomy from the polypoid lesions and from macroscopically normal antral mucosa were snap frozen in liquid nitrogen. The frozen tissue was homogenized and RNA was extracted from the homogenate (Rneasy; Qiagen, Crawley, UK). Qualitative PCR with reverse transcription for a 244-nucleotide sequence in the 5′-untranslated region was performed (COBAS Amplicor; Roche Diagnostics, Lewes, UK) according to manufacturer protocols. Tissue from the polypoid lesions contained HCV ribonucleic acid, while macroscopically normal mucosa did not. Manufacturer's positive and negative controls reacted appropriately.
Liver biopsy taken at the time of subtotal gastrectomy found mild hepatitis in the graft compatible with HCV infection (necroinflammatory grade: 1/0/1/1; fibrosis stage: 1),3 but serum concentrations of transaminase activity have remained normal to date and a further liver biopsy performed 3 years after transplant has shown no change in histological grade or staging. There is no evidence of recurrent MALToma on endoscopy or imaging studies 36 months after subtotal gastrectomy. There are no plans, currently, to initiate antiviral therapy in view of the mild histological recurrence and lack of evidence of recurrent MALToma. Antiviral therapy would be a possible future therapeutic option in the setting of HCV fibrosis progression in the allograft.
Extranodal marginal zone B-cell lymphoma arising in mucosa-associated lymphoid tissue (MALT) is termed MALToma. MALT may undergo hyperplasia due to infection with H. pylori, or secondary to autoimmune disease such as Sjögren syndrome. Reactive hyperplasia is the setting in which MALToma develops.
Extranodal marginal zone B-cell lymphoma accounts for approximately 8% of all cases of non-Hodgkin's lymphoma (NHL).4 Gastric MALToma accounts for 1% to 7% of gastric malignancies,5, 6 and in the United States has an estimated incidence of 1:30,000 to 1:80,000 among persons infected with H. pylori.7 A higher incidence in northeastern Italy (13.2:100,000) may be related to the high rate of H. pylori infection in that region.8
Conventional oncologic therapies such as chemotherapy, radiotherapy, and surgery or a combination of these modalities yield 80% to 95% 5-year survival in localized gastric MALToma.9 The observation that eradication of H. pylori infection results in regression of lymphoma10 permits more conservative treatment. After H. pylori eradication, 81% of gastric MALTomas underwent complete histologic remission at a median follow-up of 48 months.11
MALToma response to antibiotic therapy can be predicted by endoscopic ultrasound examination; MALTomas limited to the mucosa or submucosa were significantly more likely to respond than lesions invading to a deeper level.12, 13 MALToma in our patient, with transmural infiltration found on sonography, thus was unlikely to respond to H. pylori eradication, and it did not.
There is no consensus on second-line therapy (surgery, chemotherapy, or radiotherapy) for MALToma that fails to respond to H. pylori eradication as there are no published randomized studies. Accordingly, treatment decisions have to be tailored to the individual. In our patient renal disease and ascites precluded radiotherapy; antibiotic treatment thus was followed by low-dose chlorambucil that failed to induce MALToma remission. Rituximab, an antibody directed against the B-cell antigen CD20, improves response rates in 50% of patients with relapsed NHL.14 This datum has encouraged the use of rituximab in chronic lymphocytic leukemia, lymphoplasmacytic disorders, diffuse large B-cell NHL, mantle cell lymphoma, and posttransplantation lymphoproliferative disorder.15 Rituximab has been associated with reactivation of hepatitis B virus infection (albeit in conjunction with the use of other cytotoxic agents and without lamivudine prophylaxis),16, 17 but has been safely administered to patients with B-cell lymphoma and HCV infection, none of whom was cirrhotic.18 Our patient received rituximab before LT to prevent disease progression until surgical intervention was possible.
Results of a phase II study of rituximab in MALToma19 have been recently published. The response rate, according to standardized response criteria, was 73% (34 patients; 15 complete, 10 partial, 6 stable disease, 3 progressive disease).
Regression of NHL has also been reported following successful eradication of HCV infection with interferon.1 A series from Italy20 has suggested a role for HCV in the pathogenesis of MALToma, but this has not been confirmed in other series21, 22 and increased prevalence of HCV infection in patients with B-cell NHL was not associated with MALToma or gastric involvement.22 A more recent study, however, demonstrated HCV ribonucleic acid in 7 of 25 gastric MALTomas; 4 of these 7 patients had no known history of H. pylori infection.23 Approximately 1 in 20 instances of B-cell NHL may arise in association with HCV infection.24 As MALToma is uncommon, however, the role of HCV infection in causing MALToma remains unclear.
The significance of our demonstration of HCV sequences within lesional gastric mucosa, but not gastric mucosa without MALToma involvement, is unknown. Failure of successful eradication of H. pylori infection to effect lymphoma regression has been proposed to show that the low-grade lymphoproliferation is not sustained by H. pylori infection, and that HCV itself may play help to maintain B-cell expansion. In NHL, the similarity between the complementarity-determining regions of heavy and light chains and the antibodies with rheumatoid factor activity found in type II cryoglobulinemia has been demonstrated.25 The high homology of the amino acid sequences of these complementarity-determining regions to antibodies specific for E2 protein of HCV suggest that the HCV E2 protein may be the chronic antigen stimuli in same lymphomagenesis.25
Another pathogenic mechanism by which HCV may promote lymphomagenesis is the t (14;18)(q32;q21) translocation. This translocation juxtaposes the bcl-2 locus with the immunoglobulin heavy chain (IGH) locus. The resultant bcl-2 activation prevents apoptosis. Bcl-2 may also cooperate with other oncogenes such as c-myc.26 Patients with HCV-related liver disease and mixed cryoglobulinemia demonstrate a significantly higher frequency of both this translocation and resultant bcl-2 overexpression than patients with HCV-negative liver disease and chronic rheumatic disorders.27 This translocation becomes undetectable in 50% of patients with complete or partial virologic response to antiviral therapy.28 The MALT1 gene, which lies approximately 5 Mb centromeric of the bcl-2 locus, is also located at 18q21 and this translocation with the IGH locus has been reported in association with MALToma.29 The role of HCV in this translocation has not been reported.
In patients with H. pylori infection and MALToma, the current evidence supports H. pylori eradication. In patients with MALToma and HCV infection, with endosonographic findings suggestive of decreased responsiveness to H. pylori eradication, the use of antiviral therapy may be of benefit. However, at the present time, there is insufficient evidence to make a full recommendation for this treatment.
Our experience with rituximab in this patient suggests that it can be used safely in the setting of severe liver disease due to HCV infection. Rituximab may be useful in preventing progression of NHL until surgical extirpation is possible.